Patient compliance is a major consideration when pharmaceutical formulations in the form of oral solutions are to be employed. Generally, oral solutions of drugs will have a bitter or otherwise unpalatable taste. In order to make oral liquid formulations more palatable, it has been suggested to mix drug in powder form with various polymeric or wax coating agents or to microencapsulate the particles of the drug so that they may be suspended in and prevented from solubilizing in liquid for oral administration. As will be seen hereinafter, these techniques are complex, expensive and fraught with various processing and drug delivery problems.
U.S. Pat. No. 4,656,027 to Sjoovist et al. (Astra Lakemedel) discloses an oral pharmaceutical preparation which is formed by encapsulating a mixture of drug (which is normally unpalatable) and a basic substance, in a water-insoluble polymer the resulting microcapsules of which are insoluble at high pH, and adding water hereto to form the oral preparation. In an alternative embodiment, the basic substance is mixed with already encapsulated drug. Sjoovist et al indicates that the combination of the use of encapsulated drug and basic substance effectively masks the taste of the drug. Examples of basic substances employed include various hydrogen phosphates, trisodium citrate, magnesium hydroxide.
European Patent Application 0069097 (Astra Lakemedel) discloses an oral suspension formed of microencapsulated bacampicillin HCl and a basic substance such as a carbonate, for example, sodium bicarbonate, a phosphate or a citrate, whereby the otherwise bitter taste of the bacampicillin HCl is masked by encapsulating polymer and basic substance.
U.S. Pat. No. 4,865,851 to James et al discloses coating of particles of cefuroxime axetil coated with a lipid to mask bitter taste, which particles may be mixed with water to form an aqueous suspension.
U.S. Pat. No. 5,498,447 to Nishii et al discloses the coating of a wax on particles of medicament to mask unpleasant and bitter tastes.
U.S. Pat. No. 5,409,711 to Mapelli et al. (Eurand International) discloses to a pharmaceutical formulation for oral administration which includes a core containing a drug that is coated with a polymeric membrane which is soluble only at a pH of 5 or greater. An acidic compound is mixed with the coated core for reducing dissolution of the membrane in the oral cavity. The drug will be released only when the coated cores have passed through the stomach and reached the intestine where there is a pH equal to or greater than 5. The addition of the acidic compound agent is used to reduce the solubility of the polymeric membrane. The polymer membrane, in turn, provides taste masking qualities.
U.S. Pat. No. 5,653,993, to Ghanta et al. (Eurand America) teaches a procedure for microencapsulation of an NSAID drug with cellulose acetate phthalate and gelatin to mask the taste of the drug.
In each of the above patents and applications, the formulations prepared require extra processing and a polymeric physical membrane or barrier in the form of a film or encapsulation which provides the insolubility and taste masking components. The major drawback to use of a polymeric membrane is that the process involved is complicated and expensive and the dissolution of the drug may be incomplete so that release of the drug active may be inhibited resulting in lower bioavailability.
Conventional taste masking techniques such as sweeteners and flavoring agents are often used in addition to encapsulation. However, many traditional sweeteners are not effective in masking particularly unpleasant tasting drugs without the addition of another taste masking mechanism. A less complex approach for taste masking readily soluble actives would thus be a useful addition to the art.
U.S. Pat. No. 6,025,370 to Todo et al. (Toyama Chemical Co.) discloses various quinolonecarboxylic acid derivatives which covers des-quinolone (1-cycloproply-8 -(difluoromethoxy)-7-[(1R)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolonecarboxylic acid methanesulfonate monohydrate). This is a readily water soluble compound with bitter taste.